tbuckley/cabot-search huggingface dataset:
Antibody and B Cell Responses to SARS-CoV-2 Infection and Vaccination: The End of the Beginning
Authors: Katharina Röltgen, Scott D. Boyd
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

As the COVID-19 pandemic has evolved during the past years, interactions between human immune systems, rapidly mutating and selected SARS-CoV-2 viral variants, and effective vaccines have complicated the landscape of individual immunological histories. Here, we review some key findings for antibody and B cell-mediated immunity, including responses to the highly mutated omicron variants; immunological imprinting and other impacts of successive viral antigenic variant exposures on antibody and B cell memory; responses in secondary lymphoid and mucosal tissues and non-neutralizing antibody-mediated immunity; responses in populations vulnerable to severe disease such as those with cancer, immunodeficiencies, and other comorbidities, as well as populations showing apparent resistance to severe disease such as many African populations; and evidence of antibody involvement in postacute sequelae of infection or long COVID. Despite the initial phase of the pandemic ending, human populations will continue to face challenges presented by this unpredictable virus.
Genetics and Pathogenesis of Dystonia
Authors: Mirja Thomsen, Lara M. Lange, Michael Zech, Katja Lohmann
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g.,
Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML
Authors: Cheuk-Him Man, Wing Lam, Chee-Chean Dang, Xiao-yuan Zeng, Li-Chuan Zheng, Natalie Nok-Man Chan, Ka-Lam Ng, Koon-Chuen Chan, Tsz-Ho Kwok, Timothy Chi-Chun Ng, Wing-Yan Leung, Michael Shing-Yan Huen, Carmen Chak-Lui Wong, Chi Wai Eric So, Zhixun Dou, Susumu Goyama, Mark Robert Bray, Tak Wah Mak, Anskar Yu-Hung Leung
Journal: Blood (2023)

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.
Whole-genome Comparisons Identify Repeated Regulatory Changes Underlying Convergent Appendage Evolution in Diverse Fish Lineages
Authors: Heidi I Chen, Yatish Turakhia, Gill Bejerano, David M Kingsley
Journal: Molecular Biology and Evolution (2023)

Fins are major functional appendages of fish that have been repeatedly modified in different lineages. To search for genomic changes underlying natural fin diversity, we compared the genomes of 36 percomorph fish species that span over 100 million years of evolution and either have complete or reduced pelvic and caudal fins. We identify 1,614 genomic regions that are well-conserved in fin-complete species but missing from multiple fin-reduced lineages. Recurrent deletions of conserved sequences in wild fin-reduced species are enriched for functions related to appendage development, suggesting that convergent fin reduction at the organismal level is associated with repeated genomic deletions near fin-appendage development genes. We used sequencing and functional enhancer assays to confirm that PelA, a Pitx1 enhancer previously linked to recurrent pelvic loss in sticklebacks, has also been independently deleted and may have contributed to the fin morphology in distantly related pelvic-reduced species. We also identify a novel enhancer that is conserved in the majority of percomorphs, drives caudal fin expression in transgenic stickleback, is missing in tetraodontiform, syngnathid, and synbranchid species with caudal fin reduction, and alters caudal fin development when targeted by genome editing. Our study illustrates a broadly applicable strategy for mapping phenotypes to genotypes across a tree of vertebrate species and highlights notable new examples of regulatory genomic hotspots that have been used to evolve recurrent phenotypes across 100 million years of fish evolution.
Processes for identifying caregivers and screening for caregiver and patient distress in community oncology: results from WF-1803CD
Authors: Chandylen L Nightingale, Anna C Snavely, Laurie E McLouth, Emily V Dressler, Erin E Kent, Christian S Adonizio, Suzanne C Danhauer, Rachel Cannady, Judith O Hopkins, Heather Kehn, Kathryn E Weaver, Katherine R Sterba
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Despite their vital roles, informal caregivers of adult cancer patients are commonly overlooked in cancer care. This study describes processes for identifying cancer caregivers and processes for distress screening and management among caregivers and patients in the understudied community oncology setting. Methods Supportive care leaders from the National Cancer Institute Community Oncology Research Program practices completed online survey questions regarding caregiver identification, caregiver and patient distress screening, and distress management strategies. We described practice group characteristics and prevalence of study outcomes. Multivariable logistic regression explored associations between practice group characteristics and caregiver identification in the electronic health record (EHR). Results Most (64.9%, 72 of 111) supportive care leaders reported routine identification and documentation of informal caregivers; 63.8% record this information in the EHR. Only 16% routinely screen caregivers for distress, though 92.5% screen patients. Distress management strategies for caregivers and patients are widely available, yet only 12.6% are routinely identified and screened and had at least 1 referral strategy for caregivers with distress; 90.6% are routinely screened and had at least 1 referral strategy for patients. Practices with a free-standing outpatient clinic (odds ratio [OR] = 0.29, P = .0106) and academic affiliation (OR = 0.01, P = .04) were less likely to identify and document caregivers in the EHR. However, higher oncologist volume was associated with an increased likelihood of recording caregiver information in the EHR (OR = 1.04, P = .02). Conclusions Despite high levels of patient distress screening and management, few practices provide comprehensive caregiver engagement practices. Existing patient engagement protocols may provide a promising platform to build capacity to better address caregiver needs.
Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study
Authors: David A. Qualls, Nicholas Lambert, Paolo F. Caimi, Mwanasha Merrill, Priyanka Pullarkat, Richard C. Godby, David A. Bond, Graham T. Wehmeyer, Jason Romancik, Behzad Amoozgar, Lori Leslie, Loretta J. Nastoupil, Jennifer L. Crombie, Jeremy S. Abramson, Arushi Khurana, Grzegorz S. Nowakowski, Kami Maddocks, Sarah C. Rutherford, Brad Kahl, Michelle Okwali, Michael J. Buege, Venkatraman Seshan, Connie L. Batlevi, Gilles Salles
Journal: Blood (2023)
Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases
Authors: Yibo Fan, Shumei Song, Yuan Li, Shilpa S. Dhar, Jiankang Jin, Katsuhiro Yoshimura, Xiaodan Yao, Ruiping Wang, Ailing W. Scott, Melissa Pool Pizzi, Jingjing Wu, Lang Ma, George A. Calin, Samir Hanash, Linghua Wang, Michael Curran, Jaffer A. Ajani
Journal: Cancer Research (2023)

Abstract The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a “don't eat me” signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that CD47 was highly expressed on malignant PC cells, and elevated CD47 was associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 was significantly associated with diffuse type, poor differentiation, and tumor relapse. Depletion of Gal3 reduced expression of CD47 through inhibition of c-Myc binding to the CD47 promoter. Furthermore, injection of Gal3–deficient tumor cells into either wild-type and Lgals3−/− mice led to a reduction in M2 macrophages and increased T-cell responses compared with Gal3 wild-type tumor cells, indicating that tumor cell–derived Gal3 plays a more important role in GAC progression and phagocytosis than host-derived Gal3. Dual blockade of Gal3 and CD47 collaboratively suppressed tumor growth, increased phagocytosis, repolarized macrophages, and boosted T-cell immune responses. These data uncovered that Gal3 functions together with CD47 to suppress phagocytosis and orchestrate immunosuppression in GAC with PC, which supports exploring a novel combination therapy targeting Gal3 and CD47. Significance: Dual inhibition of CD47 and Gal3 enhances tumor cell phagocytosis and reprograms macrophages to overcome the immunosuppressive microenvironment and suppress tumor growth in peritoneal metastasis of gastric adenocarcinoma.
Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma
Authors: Silvia Pietrobono, Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Veronica De Vita, Federica Fazzini, Giulia Lunardi, Simona Casalino, Enza Scarlato, Valeria Merz, Camilla Zecchetto, Alberto Quinzii, Giusy Di Conza, Michael Lahn, Davide Melisi
Journal: Cancer Research (2023)

Abstract The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib. Significance: TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.
Fructose-Induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy
Authors: Yanfen Cui, Jianfei Tian, Zhaosong Wang, Hui Guo, He Zhang, Zhiyong Wang, Hui Liu, Weijie Song, Liming Liu, Ruinan Tian, Xiaoyan Zuo, Sixin Ren, Ruifang Niu, Fei Zhang
Journal: Cancer Research (2023)

Abstract Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose-deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated the AMP-activated protein kinase (AMPK)–mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose-specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in patients with PDAC. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC. Significance: Fructose activates AMPK–mTORC1 signaling to inhibit autophagy-mediated cell death in pancreatic cancer cells caused by glucose deficiency, facilitating metabolic adaptation to the tumor microenvironment and supporting tumor growth.
Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8 <sup>+</sup> T cell formation
Authors: Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung-Chi Kao, Chun-Pu Lin, Lorène Rousseau, Fu-Ti Peng, Yu-Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E. Speiser, Federica Sallusto, Ping-Chih Ho
Journal: Science Immunology (2023)

Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.
Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8 <sup>+</sup> T cell metabolic fitness and function in tumors
Authors: Jie-Feng Yang, Xudong Xing, Li Luo, Xin-Wei Zhou, Jian-Xiong Feng, Kang-Bo Huang, Huashan Liu, Shanzhao Jin, Yi-Na Liu, Shi-Hui Zhang, Yi-Hui Pan, Bing Yu, Jin-Yu Yang, Yu-Lu Cao, Yun Cao, Cliff Y. Yang, Yuan Wang, Yuxia Zhang, Jiang Li, Xiaojun Xia, Tiebang Kang, Rui-Hua Xu, Ping Lan, Jun-Hang Luo, Hui Han, Fan Bai, Song Gao
Journal: Science Immunology (2023)

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.
Letter to the Editor: Effect of tenofovir-based HIV pre-exposure prophylaxis against HBV infection in men who have sex with men
Authors: Chien-Tzu Hung, Shih-Jer Hsu, Chun-Jen Liu
Journal: Hepatology (2023)

To the editor: We read with great interest the article "Effect of tenofovir-based HIV pre-exposure prophylaxis against HBV infection in men who have sex with men" by Mizushima Daisuke et al.1 We appreciate the authors' efforts to demonstrate the prophylactic effect of tenofovir-based pre-exposure prophylaxis against HBV infection among men who have sex with men in a real-world setting. However, we believe that certain issues need to be addressed to strengthen the conclusions of the study. According to the article, the 22 participants who developed HBV infection were characterized. Among them, 3 (13.6%; case 5, case 6, and case 21) were positive for anti-HBc antibody alone and negative for both anti-HBs antibody and HBsAg.1 The serologic finding of anti-HBc positivity alone could possibly be attributed to a previous HBV infection or a false-positive result, especially in those without risk factors for HBV infection in countries with low HBV prevalence.2 Although these 3 patients had risk behavior of acquiring HBV infection, the possibility of false-positive anti-HBc could not be excluded.3,4 To exclude this possibility, the detection of serum HBV DNA would be essential. Unfortunately, data regarding the detection of serum HBV DNA was not provided. In addition, the univariate analysis in this article revealed that age, bacterial sexually transmitted infection, and the number of sexual partners at enrollment were associated with acute HBV infection. Thus, information about the subjects' sexual activity during the study period should be investigated. The lack of information on HBV vaccination is also a matter of concern. Furthermore, although the effect of tenofovir-based prophylaxis had been demonstrated, the mechanism of the prophylaxis by tenofovir was not investigated. Tenofovir could suppress HBV replication but could not prevent the entry of HBV into hepatocytes. Clarification of the mechanism would be important to support its prophylactic effect. Finally, for the confirmation of transmitting HBV infection through sexual exposure in these patients, the documentation of HBV infection from the sexual partners of the index patient and examination of the paired serum HBV genotype would be helpful.
HEXIM1 is an essential transcription regulator during human erythropoiesis
Authors: Xiurui Lv, Kristin Murphy, Zachary Murphy, Michael Getman, Nabil Rahman, Yukio Nakamura, Lionel Blanc, Patrick G. Gallagher, James Palis, Narla Mohandas, Laurie A. Steiner
Journal: Blood (2023)
Effectiveness of geriatric assessment and management in older cancer patients: a systematic review and meta-analysis
Authors: Mohammed Rashidul Anwar, Shant Torkom Yeretzian, Ana Patricia Ayala, Emma Matosyan, Henriette Breunis, Kathyrin Bote, Martine Puts, Mohammed Hassan Habib, Qixuan Li, Yeva Sahakyan, Shabbir M H Alibhai, Lusine Abrahamyan
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Frailty and multimorbidity among older cancer patients affect treatment tolerance and efficacy. Comprehensive geriatric assessment and management is recommended to optimize cancer treatment, but its effect on various outcomes remains uncertain. Objective Our objective was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) and cost-effectiveness studies comparing comprehensive geriatric assessment (with or without implementation of recommendations) to usual care in older cancer patients. Methods We searched MEDLINE, EMBASE, CINAHL, and Cochrane trials from inception to January 27, 2023, for RCTs and cost-effectiveness studies. Pooled estimates for outcomes were calculated using random-effects models. Results A total of 19 full-text articles representing 17 RCTs were included. Average participant age was 72-80 years, and 31%-62% were female. Comprehensive geriatric assessment type, mode of delivery, and evaluated outcomes varied across studies. Meta-analysis revealed no difference in risk of mortality (risk ratio [RR] = 1.08. 95% confidence interval [CI] = 0.91 to 1.29), hospitalization (RR = 0.92, 95% CI = 0.77 to 1.10), early treatment discontinuation (RR = 0.89, 95% CI = 0.67 to 1.19), initial dose reduction (RR = 0.99, 95% CI = 0.99 to 1.26), and subsequent dose reduction (RR = 0.87, 95% CI = 0.70 to 1.09). However, the risk of treatment toxicity was statistically significantly lower in the comprehensive geriatric assessment group (RR = 0.78, 95% CI = 0.70 to 0.86). No cost-effectiveness studies were identified. Conclusion Compared with usual care, comprehensive geriatric assessment was not associated with a difference in risk of mortality, hospitalization, treatment discontinuation, and dose reduction but was associated with a lower risk of treatment toxicity indicating its potential to optimize cancer treatment in this population. Further research is needed to evaluate cost-effectiveness.